Dr. Ecstasy

By DRAKE BENNETT

Alexander Shulgin, Sasha to his friends, lives with his wife, Ann, 30 minutes inland from the San Francisco Bay on a hillside dotted with valley oak, Monterey pine and hallucinogenic cactus. At 79, he stoops a little, but he is still well over six feet tall, with a mane of white hair, a matching beard and a wardrobe that runs toward sandals, slacks and short-sleeved shirts with vaguely ethnic patterns. He lives modestly, drawing income from a small stock portfolio supplemented by his Social Security and the rent that two phone companies pay him to put cell towers on his land. In many respects he might pass for a typical Contra Costa County retiree.

It was an acquaintance of Shulgin's named Humphry Osmond, a British psychiatrist and researcher into the effects of mescaline and LSD, who coined the word ''psychedelic'' in the late 1950's for a class of drugs that significantly alter one's perception of reality. Derived from Greek, the term translates as ''mind manifesting'' and is preferred by those who believe in the curative power of such chemicals. Skeptics tend to call them hallucinogens.

Shulgin is in the former camp. There's a story he likes to tell about the past 100 years: ''At the beginning of the 20th century, there were only two psychedelic compounds known to Western science: cannabis and mescaline. A little over 50 years later -- with LSD, psilocybin, psilocin, TMA, several compounds based on DMT and various other isomers -- the number was up to almost 20. By 2000, there were well over 200. So you see, the growth is exponential.'' When I asked him whether that meant that by 2050 we'll be up to 2,000, he smiled and said, ''The way it's building up now, we may have well over that number.''

The point is clear enough: the continuing explosion in options for chemical mind-manifestation is as natural as the passage of time. But what Shulgin's narrative leaves out is the fact that most of this supposedly inexorable diversification took place in a lab in his backyard. For 40 years, working in plain sight of the law and publishing his results, Shulgin has been a one-man psychopharmacological research sector. (Timothy Leary called him one of the century's most important scientists.) By Shulgin's own count, he has created nearly 200 psychedelic compounds, among them stimulants, depressants, aphrodisiacs, ''empathogens,'' convulsants, drugs that alter hearing, drugs that slow one's sense of time, drugs that speed it up, drugs that trigger violent outbursts, drugs that deaden emotion -- in short, a veritable lexicon of tactile and emotional experience. And in 1976, Shulgin fished an obscure chemical called MDMA out of the depths of the chemical literature and introduced it to the wider world, where it came to be known as Ecstasy.

In the small subculture that truly believes in better living through chemistry, Shulgin's oeuvre has made him an icon and a hero: part pioneer, part holy man, part connoisseur. As his supporters point out, his work places him in an old, and in many cultures venerable, tradition. Whether it's West African iboga ceremonies or Navajo peyote rituals, 60's LSD culture or the age-old cultivation of cannabis nearly everywhere on the planet it can grow, the pursuit and celebration of chemically-induced alternate realms of consciousness goes back beyond the dawn of recorded history and has proved impossible to fully suppress. Shulgin sees nothing strange about devoting his life to it. What's strange to him is that so few others see fit to do the same thing.

Most of the scientific community considers Shulgin at best a curiosity and at worst a menace. Now, however, near the end of his career, his faith in the potential of psychedelics has at least a chance at vindication. A little more than a month ago, the Food and Drug Administration approved a Harvard Medical School study looking at whether MDMA can alleviate the fear and anxiety of terminal cancer patients. And next month will mark a year since Michael Mithoefer, a psychiatrist in Charleston, S.C., started his study of Ecstasy-assisted therapy for post-traumatic stress disorder. At the same time, with somewhat less attention, studies at the Harbor-U.C.L.A. Medical Center and the University of Arizona, Tucson, have focused on the therapeutic potential of psilocybin (the active ingredient in ''magic mushrooms''). It's far from a revolution, but it is an opening, and as both scientist and advocate, Shulgin has helped create it. If -- and it's a big ''if'' -- the results of the studies are promising enough, it might bring something like legitimacy to the Shulgin pharmacopoeia.

"I've always been interested in the machinery of the mental process,'' Shulgin told me not long ago. He has also, from a very young age, loved playing with chemicals. As a lonely 16-year-old Harvard scholarship student soon to drop out and join the Navy, he studied organic chemistry. His interest in pharmacology dates to 1944, when a military nurse gave him some orange juice just before his surgery for a thumb infection. Convinced that the undissolved crystals at the bottom of the glass were a sedative, Shulgin fell unconscious, only to find upon waking that the substance had been sugar. It was a revelatory, tantalizing hint of the mind's odd strength.

When Shulgin had his first psychedelic experience in 1960, he was a young U.C. Berkeley biochemistry Ph.D. working at Dow Chemical. He had already been interested for several years in the chemistry of mescaline, the active ingredient in peyote, when one spring day a few friends offered to keep an eye on him while he tried it himself. He spent the afternoon enraptured by his surroundings. Most important, he later wrote, he realized that everything he saw and thought ''had been brought about by a fraction of a gram of a white solid, but that in no way whatsoever could it be argued that these memories had been contained within the white solid. . . . I understood that our entire universe is contained in the mind and the spirit. We may choose not to find access to it, we may even deny its existence, but it is indeed there inside us, and there are chemicals that can catalyze its availability.''

Epiphanies don't come much grander than that, and Shulgin's interest in psychoactive drugs bloomed into an obsession. ''There was,'' he remembers thinking, ''this remarkably rich and unexplored area that I had to explore.'' Two years later, he was given his chance when he created Zectran, one of the world's first biodegradable insecticides. In return, Dow gave him its customary dollar for the patent and unlimited freedom to pursue his interests.

As Shulgin turned toward making psychedelics, Dow remained true to its word. When the company asked, he patented his compounds. When it didn't, Shulgin published his findings in places like Nature and The Journal of Organic Chemistry. Eventually, however, Dow decided that Shulgin's work wasn't something it wanted to endorse and asked that he not use the company address in his publications. He began to work out of a lab he had set up at home, eventually leaving Dow altogether to freelance as a consultant to research labs and hospitals.

All along he made drugs: 2,5-dimethoxy-4-ethoxyamphetamine, or MEM for short, was his Rosetta stone, a ''valuable and dramatic compound'' that opened the door to a whole class of drugs based on changes at the ''4 position'' of a molecule's central carbon ring. A compound he dubbed Aleph-1 gave him ''one of the most delicious blends of inflation, paranoia and selfishness that I have ever experienced.'' Another, Ariadne, was patented and tested under the name Dimoxamine as a drug for ''restoring motivation in senile geriatric patients.'' Still another, DIPT, created no visual hallucinations but distorted the user's sense of pitch.

Shulgin tested for activity by taking the chemicals himself. He would start many times below the active dose of a compound's closest analog and work his way up on alternate days. When he found something of interest, Ann, whom he married in 1981, would try it. If he thought further study was warranted, he would invite over his ''research group'' of six to eight close friends -- among them two psychologists and a fellow chemist -- and try the drugs out on them. In case of a truly dangerous reaction, Shulgin kept an anti-convulsant on hand. He used it twice, both times on himself.

Shulgin's pace has slowed recently -- the research group hardly meets anymore. Nevertheless, Ann figures that she's had more than 2,000 psychedelic experiences. Shulgin puts his own figure above 4,000. Asked if they had suffered any effects from their remarkable drug histories, they laughed. ''You mean negative effects?'' Ann said. In more than a dozen hours of conversation, her memory proved sharp. But Shulgin, while a nimble conversationalist, can have trouble with names -- of people and places, never chemicals. At one point, while explaining a mnemonic device he uses to remember world geography, he paused and asked me, ''Where's that place where Ann is from?'' (She was born in New Zealand.) He is, though, also nearing 80.

Once a Shulgin compound develops a reputation, it is almost invariably placed on the Drug Enforcement Agency's list of Schedule I drugs, those deemed to have no accepted medical use and the highest potential for abuse or addiction. It is therefore rather striking that Shulgin is not only still a free man, but also still at work. His own explanation is that, quite simply, ''I'm not doing anything illegal.'' For more than 20 years, until a government crackdown, he had a D.E.A.-issued Schedule I research license. And many of the drugs in his lab weren't illegal because they hadn't existed until he created them.

Shulgin's knack for befriending the right people hasn't hurt. A week after I visited him, he was headed to Sonoma County for the annual ''summer encampment'' of the Bohemian Club, an exclusive, secretive San Francisco-based men's club that has counted every Republican president since Herbert Hoover among its members.

For a long time, though, Shulgin's most helpful relationship was with the D.E.A. itself. The head of the D.E.A.'s Western Laboratory, Bob Sager, was one of his closest friends. Sager officiated at the Shulgins' wedding and, a year later, was married on Shulgin's lawn. Through Sager, the agency came to rely on Shulgin: he would give pharmacology talks to the agents, make drug samples for the forensic teams and serve as an expert witness -- though, he is quick to point out, he appeared much more frequently for the defense. He even wrote the definitive law-enforcement desk-reference work on controlled substances. In his office, Shulgin has several plaques awarded to him by the agency for his service. (Shulgin denies that this had anything to do with his being given his Schedule I license.)

Nevertheless, in the early 80's, Shulgin began having grim fantasies of the D.E.A. throwing him in jail, ransacking his lab and destroying all of his records. At the same time, he was finding it harder to get his work published: journals were either uninterested in or leery about human psychedelic research. He decided to make as much of what he knew public as quickly as possible. He and Ann started work on a book called ''PiHKAL'' (short for ''Phenethylamines I Have Known and Loved,'' after a family of compounds particularly rich in psychoactivity), self-publishing it in 1991.

It is a curious hybrid work, divided into two sections. The first, ''The Love Story,'' is a thinly fictionalized account of Sasha's and Ann's comings of age, previous marriages, meeting, courtship (to which nearly 200 pages are devoted) and many drug experiences. The second, ''The Chemical Story,'' is not a story at all, but capsule descriptions of 179 phenethylamines. Each entry includes step-by-step instructions for synthesis, along with recommended dosages, duration of action and ''qualitative comments'' like the following, for 60 milligrams of something called 3C-E: ''Visuals very strong, insistent. Body discomfort remained very heavy for first hour. . . . 2nd hour on, bright colors, distinct shapes -- jewel-like -- with eyes closed. Suddenly it became clearly not anti-erotic. . . . Image of glass-walled apartment building in mid-desert. Exquisite sensitivity. Down by? midnight. Next morning, faint flickering lights on looking out windows.'' ''TiHKAL'' (''Tryptamines I Have Known and Loved''), self-published six years later, follows the same model.

To date, ''PiHKAL'' has sold more than 41,000 copies, a figure nearly unheard-of for a self-published book. It introduced Shulgin's work to a whole new audience and turned him into an underground celebrity. An organization called the Center for Cognitive Liberty and Ethics has an online Ask Dr. Shulgin column that receives 200 questions a month. On independent drug-information Web sites like www.erowid.com, you can find the ''PiHKAL'' and ''TiHKAL'' entries for dozens of drugs, along with many anonymously posted accounts of Shulgin-style self-dosing drug experiments, some of them harrowing in their recklessness.

With all of these fellow travelers, some very bad experiences are inevitable. In 1967, a Shulgin compound called DOM enjoyed a brief vogue in Haight-Ashbury under the name STP, at doses several times larger than those at which Shulgin had found significant psychoactive effects, and emergency rooms saw a spike in the number of people coming in thinking they would never come down. And while the number of psychedelic-related deaths is orders of magnitude smaller than the number due to alcohol, prescription drugs or even over-the-counter painkillers, they do occur regularly. In October 2000, a 20-year-old man in Norman, Okla., died from taking 2C-T-7, a drug Shulgin describes in ''PiHKAL'' as ''good and friendly and wonderful.''

When I asked Shulgin whether he remembered the first time he heard that someone had died from one of his drugs, he said he did not: ''It would have struck me as being a sad event. And yet, at the same time, how many people die from aspirin? It's a small but real percentage.'' (The American Association of Poison Control Centers, whose numbers are not comprehensive, attributed 59 deaths to aspirin in 2003; most, though, were suicides.) Asked whether he could imagine a drug so addictive that it should be banned, he said no. With his fervent libertarianism -- he says the only appropriate restriction on drugs is one to prevent children from buying them -- he has inoculated himself against any sense of personal guilt.

Shulgin's special relationship with the D.E.A. ended two years after the publication of ''PiHKAL.'' According to Richard Meyer, spokesman for the agency's San Francisco Field Division: ''It is our opinion that those books are pretty much cookbooks on how to make illegal drugs. Agents tell me that in clandestine labs that they have raided, they have found copies of those books.'' In 1993, D.E.A. agents descended on Shulgin's farm, combed through the house and lab and carted off anything they thought might be an illicit substance. Shulgin was fined $25,000 for violations of the terms of his Schedule I license (donations from friends and admirers ended up covering the whole amount) and was asked to turn the license in.

To the extent that Shulgin is known to the wider world, it is as the godfather of Ecstasy: 3,4-methylenedioxy-N-methylamphetamine, or MDMA, was originally patented in 1914 by Merck. The byproduct of a chemical synthesis, it was thought to have no use of its own and was promptly forgotten. But Shulgin resynthesized it in 1976 at the suggestion of a former student. (He has never found out how she heard about it.) Two years later, in a paper written with his friend and fellow chemist David Nichols, he was the first to publicly document its effect on humans: ''an easily controlled altered state of consciousness with emotional and sensual overtones.''

Unlike many of its subsequent users, Shulgin did not find his MDMA experience transformative. For him the effect was like a particularly lucid alcohol buzz; he called it his ''low-calorie martini.'' He was intrigued, though, by the drug's unique combination of intoxication, disinhibition and clarity. ''It didn't have the other visual and auditory imaginative things that you often get from psychedelics,'' he said. ''It opened up a person, both to other people and inner thoughts, but didn't necessarily color it with pretty colors and strange noises.'' He decided that it might be well suited for psychotherapy.

At the time, it was not such an unconventional idea. In the 50's and 60's, the use of LSD, psilocybin and mescaline in therapy was the subject of much mainstream scholarly debate. LSD was a particularly hot topic: more than a thousand papers were written on its use as an experimental treatment for alcoholism, depression and various neuroses in some 40,000 patients. One proponent was a psychotherapist and friend of Shulgin's named Leo Zeff. When Shulgin had him try MDMA in 1977, Zeff was so impressed that he came out of retirement to proselytize for it. Ann Shulgin remembers a speaker at Zeff's memorial service saying that Zeff had introduced the drug to ''about 4,000'' therapists.

In certain therapeutic circles, MDMA acquired a reputation as a wonder drug. Anecdotal accounts attested to its ability to induce in one session the sort of breakthroughs that normally took months or years of therapy. According to George Greer, a psychiatrist who in the early 80's conducted MDMA therapy sessions with 80 patients, ''Without exception, every therapist who I talked to or even heard of, every therapist who gave MDMA to a patient, was highly impressed by the results.''

But the drug was also showing up in nightclubs in Dallas and Los Angeles, and in 1986 the D.E.A. placed it in Schedule I. By the late 90's, household surveys showed millions of teenagers and college students using it, and in 2000, U.S. Customs officials seized nearly 10 million pills. Parents and public officials worried that a whole generation was consigning itself to a life of drug-induced depression and cognitive decay.

There is, in fact, little consensus about what MDMA does to your brain over the long run. Researchers generally agree on its immediate physiological effects: especially at higher doses, it can trigger sharp increases in muscle tension, heart rate and blood pressure. Hyperthermia, or raised body temperature, is a particular worry, along with the attendant risk of heatstroke or dehydration. MDMA also, at least temporarily, exhausts the brain's supply of serotonin (a neurochemical thought to play a role in memory and mood regulation). But as to the extent and duration of that depletion, and whether it has any measurable functional or behavioral consequences, there is fierce debate and surprisingly scarce data. Nationwide, fatality numbers are hard to come by, but a study by New York City's deputy chief medical examiner determined that of the 19,000 deaths from all causes reported to his office between January 1997 and June 2000, 2 were due solely to Ecstasy.

In the past couple of years, MDMA's opponents have backed off from some of their stronger claims. (In one particularly embarrassing instance, a study linking MDMA to Parkinson's disease was revealed to have instead been based on the use of methamphetamine, which is known to be much more neurotoxic.) Emboldened, a few psychiatrists are bringing MDMA back into the news in a role closer to the one Shulgin originally imagined for it.

With the F.D.A.'s approval of the Harvard cancer-patient study on Dec. 17, all that's still needed is a D.E.A. license for MDMA. John Halpern, the psychiatrist heading the study, anticipates that happening in the next couple of months. At the same time, he cautions against making too much of his ''small pilot study'': eight subjects undergoing a course of MDMA therapy, with another four receiving a placebo. The Charleston study is similarly modest, with 20 subjects.

Still, according to Mark A.R. Kleiman, director of the Drug Policy Analysis Program at U.C.L.A., ''there's obviously been a significant shift at the regulatory agencies and the Institutional Review Boards. There are studies being approved that wouldn't have been approved 10 years ago. And there are studies being proposed that wouldn't have been proposed 10 years ago.''

The theoretical basis for MDMA therapy varies a bit depending on whom you talk to. Greer says that by lowering patients' defenses, the drug allows them to face troubling, even repressed, memories. Charles Grob, the psychiatry professor running the U.C.L.A. psilocybin study (also with terminal cancer patients) and a longtime advocate of therapeutic MDMA research, focuses more on the ''empathic rapport'' catalyzed by MDMA. ''I don't know of any other compound that can achieve this to the degree that MDMA can,'' he said.

The medical community remains dubious. For Vivian Rakoff, emeritus professor of psychiatry at the University of Toronto, there is something familiar about the claims being made for psychedelics. ''The notion of the revelatory moment due to some drug or maneuver that will allow you to change your life has been around for a long time,'' he said. ''Every few years, something comes along that claims to be what Freud called the 'royal road to the unconscious.''' Steven Hyman, professor of neurobiology at Harvard Medical School and former director of the National Institute of Mental Health, put it this way: ''If you asked me to place a bet, I would be skeptical. In general, one worries that insights gained under states of disinhibition or mild euphoria or different cognitive states with illusions may seem strange and distant from the vantage of our ordinary life.'' Even so, both Hyman and Rakoff say that research should be allowed to proceed.

Shulgin has been credited with jump-starting today's therapeutic research, but he prefers to play down his role. While heartened by the MDMA studies and happy to play psychedelic elder statesman, he insists that he is not a healer or a shaman but a researcher. Asked why he does what he does, he replies, ''I'm curious!'' He is most animated when describing the feeling that accompanies the discovery of a new compound, no matter what its properties. Sometimes he compares the moment to that of artistic creation (''The pleasure of composing a new painting or piece of music''), and sometimes it sounds more like a close encounter of the third kind (''You're meeting something you don't know, and it's meeting something it doesn't know. And so you have this exchange of properties and ideas'').

Shulgin's lab is in the concrete-block foundation of what used to be a small cabin, set into a ridge a few dozen yards from his house along a narrow brick path. On the door is a laminated sign that reads, ''This is a research facility that is known to and authorized by the Contra Costa County Sheriff's Office, all San Francisco D.E.A. Personnel and the State and Federal E.P.A. Authorities.'' Underneath are phone numbers for the relevant official at each agency. He posted it after the sheriff's department and the D.E.A. raided the farm a second time a few years ago. (They later apologized.)

Shulgin gave me my tour late one afternoon. A weak light came in through the small, dusty windows. The smell -- synthetic and organic at once, like a burning tire doused in urine -- took some getting used to. Bulbous flasks were clipped into place above a counter crowded with glassware shaped like finds from the Burgess Shale. ''Everything you need is right here,'' Shulgin declared, pulling out drawer after clattering drawer of test tubes, beakers, plastic tubing and syringes. At the far end of the room, beside the fireplace, was a small chalkboard covered with the traces of his brainstorming -- antennaed pentagons and hexagons ringed with N's, H's, C's and O's. Shulgin picked a short bit of scrap wood off the counter. He occasionally used it, he explained, to tear down the spider webs that festooned the rafters. ''But the main problem is the squirrels,'' he said, pointing to where he had put up sheet metal to keep them out. ''It doesn't look like the labs you see in the movies, but you get a chemist out here, and he'll say, 'Oh, my God, I'd love to have a lab like this.'''

Of course, in a way, it's exactly the sort of lab that you see in the movies -- they're just movies in which the scientists wear frock coats, turn into monsters and abduct wan women in nightgowns. There's an undeniable romance to what Shulgin does. As he stood there with his spider-web stick, describing what it's like to be in the lab late on a cold night with the fire blazing and Rachmaninoff on the radio, it seemed to me that he realized it.

He might best be described not as a scientist in the modern sense but as a different type -- what Aldous Huxley, the novelist turned psychedelic philosopher, once described as a ''naturalist of the mind,'' a ''collector of psychological specimens'' whose ''primary concern was to make a census, to catch, kill, stuff and describe as many kinds of beasts as he could lay his hands on.'' Shulgin has on occasion run PET scans to see where in the brain some of his drugs go. He has offered theories as to mechanisms of action or, as with MDMA, even suggested an application for a drug. But his primary purpose, as he sees it, is not to worry about things like that -- much less about the political and social consequences of his creations. His job is to be first and then push on somewhere new. What to do with the widening wake of chemicals he leaves behind is for the rest of us to figure out.